RESUMEN
Evidence suggests that early trauma may have a negative effect on cognitive functioning in individuals with psychosis, yet the relationship between childhood trauma and cognition among those at clinical high risk (CHR) for psychosis remains unexplored. Our sample consisted of 626 CHR children and 279 healthy controls who were recruited as part of the North American Prodrome Longitudinal Study 2. Childhood trauma up to the age of 16 (psychological, physical, and sexual abuse, emotional neglect, and bullying) was assessed by using the Childhood Trauma and Abuse Scale. Multiple domains of cognition were measured at baseline and at the time of psychosis conversion, using standardized assessments. In the CHR group, there was a trend for better performance in individuals who reported a history of multiple types of childhood trauma compared with those with no/one type of trauma (Cohen d = 0.16). A history of multiple trauma types was not associated with greater cognitive change in CHR converters over time. Our findings tentatively suggest there may be different mechanisms that lead to CHR states. Individuals who are at clinical high risk who have experienced multiple types of childhood trauma may have more typically developing premorbid cognitive functioning than those who reported minimal trauma do. Further research is needed to unravel the complexity of factors underlying the development of at-risk states.
Asunto(s)
Acoso Escolar , Trastornos Psicóticos , Niño , Cognición , Humanos , Estudios Longitudinales , Síntomas ProdrómicosRESUMEN
BACKGROUND: Severity of negative symptoms has been associated with poor functioning, cognitive deficits, and defeatist beliefs in schizophrenia patients. However, one area that remains understudied is persistent negative symptoms (PNS). Negative symptoms, including PNS, have been observed in those at clinical high-risk (CHR) for psychosis. The aim of this study was to determine if PNS were associated with functioning, neurocognition, and defeatist beliefs in a CHR sample. METHOD: CHR participants (n = 764) were recruited for the North American Prodrome Longitudinal Study. Negative symptoms were rated on the Scale of Psychosis-risk Symptoms. Generalized linear mixed models for repeated measures were used to examine changes over time between and within groups (PNS vs non-PNS). RESULTS: The PNS group (n = 67) had significant deficits in functioning at baseline, 6, 12, 18, and 24-months compared to the non-PNS group (n = 673). Functioning improved over time in the non-PNS group, while functioning in the PNS group remained relatively stable and poor over a two-year period. A consistent trend emerged demonstrating higher defeatist beliefs in the PNS group; however, this result was lost when controlling for persistent depressive symptoms. There were no significant differences between the groups on neurocognition, social cognition, and transition to psychosis. CONCLUSIONS: PNS exist in youth at CHR for psychosis, resulting in significant and persistent functional impairment, which remains when controlling for persistent depressive symptoms. PNS remain even in CHR youth who do not transition to psychosis. Thus, PNS may represent an unmet therapeutic need in CHR populations for which there are currently no effective treatments.
Asunto(s)
Trastornos del Conocimiento , Trastornos Psicóticos , Esquizofrenia , Adolescente , Humanos , Estudios Longitudinales , Síntomas Prodrómicos , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/epidemiología , Esquizofrenia/complicaciones , Esquizofrenia/epidemiologíaRESUMEN
Social cognition deficits have been observed in individuals at clinical high risk (CHR) for psychosis. Longitudinal change in social cognition were analyzed in CHR individuals from the North American Prodrome Longitudinal Study (NAPLS2) based on outcome at 24â¯months. Individuals (nâ¯=â¯359) were classified into remission, symptomatic, prodromal progression and transition to psychosis (CHR-T) groups. Social cognition was assessed using theory of mind, emotion perception, and social perception tasks. There were no differences at baseline or 24â¯months between the groups on social cognition. Non-transition groups improved significantly over time on social cognition, but CHR-T did not show this effect.
Asunto(s)
Progresión de la Enfermedad , Emociones/fisiología , Reconocimiento Facial/fisiología , Síntomas Prodrómicos , Trastornos Psicóticos/fisiopatología , Percepción Social , Teoría de la Mente/fisiología , Adulto , Expresión Facial , Femenino , Humanos , Estudios Longitudinales , Masculino , Inducción de Remisión , Riesgo , Adulto JovenRESUMEN
Both neurocognitive deficits and schizophrenia are highly heritable. Genetic overlap between neurocognitive deficits and schizophrenia has been observed in both the general population and in the clinical samples. This study aimed to examine if the polygenic architecture of susceptibility to schizophrenia modified neurocognitive performance in schizophrenia patients. Schizophrenia polygenic risk scores (PRSs) were first derived from the Psychiatric Genomics Consortium (PGC) on schizophrenia, and then the scores were calculated in our independent sample of 1130 schizophrenia trios, who had PsychChip data and were part of the Schizophrenia Families from Taiwan project. Pseudocontrols generated from the nontransmitted parental alleles of the parents in these trios were compared with alleles in schizophrenia patients in assessing the replicability of PGC-derived susceptibility variants. Schizophrenia PRS at the P-value threshold (PT) of 0.1 explained 0.2% in the variance of disease status in this Han-Taiwanese samples, and the score itself had a P-value 0.05 for the association test with the disorder. Each patient underwent neurocognitive evaluation on sustained attention using the continuous performance test and executive function using the Wisconsin Card Sorting Test. We applied a structural equation model to construct the neurocognitive latent variable estimated from multiple measured indices in these 2 tests, and then tested the association between the PRS and the neurocognitive latent variable. Higher schizophrenia PRS generated at the PT of 0.1 was significantly associated with poorer neurocognitive performance with explained variance 0.5%. Our findings indicated that schizophrenia susceptibility variants modify the neurocognitive performance in schizophrenia patients.
Asunto(s)
Trastornos Neurocognitivos/genética , Esquizofrenia/genética , Adulto , Alelos , Función Ejecutiva/fisiología , Familia , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Herencia Multifactorial/genética , Pruebas Neuropsicológicas , Polimorfismo de Nucleótido Simple , Factores de Riesgo , TaiwánRESUMEN
Schizophrenia's (SZ's) heritability and familial transmission have been known for several decades; however, despite the clear evidence for a genetic component, it has been very difficult to pinpoint specific causative genes. Even so genetic studies have taught us a lot, even in the pregenomic era, about the molecular underpinnings and disease-relevant pathways. Recurring themes emerged revealing the involvement of neurodevelopmental processes, glutamate regulation, and immune system differential activation in SZ etiology. The recent emergence of epigenetic studies aimed at shedding light on the biological mechanisms underlying SZ has provided another layer of information in the investigation of gene and environment interactions. However, this epigenetic insight also brings forth another layer of complexity to the (epi)genomic landscape such as interactions between genetic variants, epigenetic marks-including cross-talk between DNA methylation and histone modification processes-, gene expression regulation, and environmental influences. In this review, we seek to synthesize perspectives, including limitations and obstacles yet to overcome, from genetic and epigenetic literature on SZ through a qualitative review of risk factors and prevailing hypotheses. Encouraged by the findings of both genetic and epigenetic studies to date, as well as the continued development of new technologies to collect and interpret large-scale studies, we are left with a positive outlook for the future of elucidating the molecular genetic mechanisms underlying SZ and other complex neuropsychiatric disorders.
Asunto(s)
Epigénesis Genética , Predisposición Genética a la Enfermedad , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Metilación de ADN , Ambiente , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Código de Histonas , Humanos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Factores de Riesgo , Esquizofrenia/etiologíaRESUMEN
The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.
Asunto(s)
Receptores de Dopamina D2/genética , Esquizofrenia/genética , Adulto , Alelos , Empalme Alternativo/genética , Encéfalo/metabolismo , China , Cognición/fisiología , Etnicidad/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Precursores del ARN/metabolismo , Empalme del ARN , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Receptores de Dopamina D2/metabolismo , Factores de Riesgo , Esquizofrenia/metabolismoRESUMEN
BACKGROUND: The Harvard Adolescent Family High Risk (FHR) Study examined multiple domains of function in young relatives of individuals diagnosed with schizophrenia to identify precursors of the illness. One such area is motor performance, which is deviant in people with schizophrenia and in children at risk for schizophrenia, usually offspring. The present study assessed accuracy of motor performance and degree of lateralization in FHR adolescents and young adults. METHODS: Subjects were 33 non-psychotic, first-degree relatives of individuals diagnosed with schizophrenia, and 30 non-psychotic comparison subjects (NpC), ranging in age from 13 to 25 who were compared using a line-drawing task. RESULTS: FHR individuals exhibited less precise and coordinated line drawing but greater degree of lateralization than controls. Performance on the linedrawing task was correlated with degree of genetic loading, a possible predictor of higher risk for schizophrenia in the pedigree. CONCLUSIONS: The observation of increased motor deviance and increased lateralization in FHR can be utilized in identification and initiation of the treatment in those at high risk in order to prevent or delay the full manifestation of this devastating condition. The use of a rigorously quantified measure is likely to add to the sensitivity of measuring motor performance, especially when impairments may be subtle.
Asunto(s)
Salud de la Familia , Trastornos Psicomotores , Esquizofrenia/complicaciones , Adolescente , Adulto , Femenino , Lateralidad Funcional , Humanos , Masculino , Pruebas Neuropsicológicas , Trastornos Psicomotores/diagnóstico , Trastornos Psicomotores/etiología , Trastornos Psicomotores/genética , Riesgo , Esquizofrenia/genética , Adulto JovenRESUMEN
Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽ 1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P = 1.5 × 10(-)(4)). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽ 0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P = 0.018) and de novo mutations (P = 0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N = 614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.
Asunto(s)
Exoma/genética , Genes Recesivos/genética , Esquizofrenia/genética , Estudios de Casos y Controles , Familia , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Heterocigoto , Homocigoto , Humanos , Masculino , Canales de Sodio Activados por Voltaje/genéticaRESUMEN
The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD.
Asunto(s)
Redes Reguladoras de Genes , Inmunidad Innata/genética , Personal Militar , Trastornos por Estrés Postraumático/genética , Expresión Génica , Humanos , Masculino , Trastornos por Estrés Postraumático/diagnóstico , Adulto JovenRESUMEN
BACKGROUND: A series of research reports has indicated that the use of substances such as cannabis, alcohol and tobacco are higher in youth at clinical high risk (CHR) of developing psychosis than in controls. Little is known about the longitudinal trajectory of substance use, and findings on the relationship between substance use and later transition to psychosis in CHR individuals are mixed. METHOD: At baseline and 6- and 12-month follow-ups, 735 CHR and 278 control participants completed the Alcohol and Drug Use Scale and a cannabis use questionnaire. The longitudinal trajectory of substance use was evaluated with linear mixed models. RESULTS: CHR participants endorsed significantly higher cannabis and tobacco use severity, and lower alcohol use severity, at baseline and over a 1-year period compared with controls. CHR youth had higher lifetime prevalence and frequency of cannabis, and were significantly younger upon first use, and were more likely to use alone and during the day. Baseline substance use did not differentiate participants who later transitioned to psychosis (n = 90) from those who did not transition (n = 272). Controls had lower tobacco use than CHR participants with a prodromal progression clinical outcome and lower cannabis use than those with a psychotic clinical outcome at the 2-year assessment. CONCLUSIONS: In CHR individuals cannabis and tobacco use is higher than in controls and this pattern persists across 1 year. Evaluation of clinical outcome may provide additional information on the longitudinal impact of substance use that cannot be detected through evaluation of transition/non-transition to psychosis alone.
Asunto(s)
Síntomas Prodrómicos , Trastornos Psicóticos/diagnóstico , Trastornos Relacionados con Sustancias/clasificación , Trastornos Relacionados con Sustancias/epidemiología , Adolescente , Adulto , Cannabis , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Modelos Lineales , Estudios Longitudinales , Masculino , Escalas de Valoración Psiquiátrica , Factores de Riesgo , Índice de Severidad de la Enfermedad , Nicotiana , Adulto JovenRESUMEN
BACKGROUND: Previous studies suggest that abnormalities in maternal immune activity during pregnancy alter the offspring's brain development and are associated with increased risk for schizophrenia (SCZ) dependent on sex. METHOD: Using a nested case-control design and prospectively collected prenatal maternal sera from which interleukin (IL)-1ß, IL-8, IL-6, tumor necrosis factor (TNF)-α and IL-10 were assayed, we investigated sex-dependent associations between these cytokines and 88 psychotic cases [SCZ = 44; affective psychoses (AP) = 44] and 100 healthy controls from a pregnancy cohort followed for > 40 years. Analyses included sex-stratified non-parametric tests adjusted for multiple comparisons to screen cytokines associated with SCZ risk, followed by deviant subgroup analyses using generalized estimating equation (GEE) models. RESULTS: There were higher prenatal IL-6 levels among male SCZ than male controls, and lower TNF-α levels among female SCZ than female controls. The results were supported by deviant subgroup analyses with significantly more SCZ males with high IL-6 levels (>highest quartile) compared with controls [odd ratio (OR)75 = 3.33, 95% confidence interval (CI) 1.13-9.82], and greater prevalence of low TNF-α levels (Asunto(s)
Trastornos Psicóticos Afectivos/etiología
, Citocinas/sangre
, Complicaciones del Embarazo/inmunología
, Efectos Tardíos de la Exposición Prenatal/inmunología
, Trastornos Psicóticos/etiología
, Esquizofrenia/etiología
, Adulto
, Estudios de Casos y Controles
, Estudios de Cohortes
, Femenino
, Humanos
, Masculino
, Embarazo
, Factores Sexuales
RESUMEN
BACKGROUND: Persons developing schizophrenia (SCZ) manifest various pre-morbid neuropsychological deficits, studied most often by measures of IQ. Far less is known about pre-morbid neuropsychological functioning in individuals who later develop bipolar psychoses (BP). We evaluated the specificity and impact of family history (FH) of psychosis on pre-morbid neuropsychological functioning. METHOD: We conducted a nested case-control study investigating the associations of neuropsychological data collected systematically at age 7 years for 99 adults with psychotic diagnoses (including 45 SCZ and 35 BP) and 101 controls, drawn from the New England cohort of the Collaborative Perinatal Project (CPP). A mixed-model approach evaluated full-scale IQ, four neuropsychological factors derived from principal components analysis (PCA), and the profile of 10 intelligence and achievement tests, controlling for maternal education, race and intra-familial correlation. We used a deviant responder approach (<10th percentile) to calculate rates of impairment. RESULTS: There was a significant linear trend, with the SCZ group performing worst. The profile of childhood deficits for persons with SCZ did not differ significantly from BP. Neuropsychological impairment was identified in 42.2% of SCZ, 22.9% of BP and 7% of controls. The presence of psychosis in first-degree relatives (FH+) significantly increased the severity of childhood impairment for SCZ but not for BP. CONCLUSIONS: Pre-morbid neuropsychological deficits are found in a substantial proportion of children who later develop SCZ, especially in the SCZ FH+ subgroup, but less so in BP, suggesting especially impaired neurodevelopment underlying cognition in pre-SCZ children. Future work should assess genetic and environmental factors that explain this FH effect.
Asunto(s)
Trastorno Bipolar/fisiopatología , Pruebas Neuropsicológicas , Esquizofrenia/fisiopatología , Adulto , Trastorno Bipolar/genética , Estudios de Casos y Controles , Niño , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , New England , Esquizofrenia/genética , Índice de Severidad de la EnfermedadRESUMEN
We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.
Asunto(s)
Estudios de Asociación Genética/estadística & datos numéricos , Predisposición Genética a la Enfermedad/genética , Genómica/estadística & datos numéricos , Esquizofrenia/genética , Animales , Estudios de Casos y Controles , Bases de Datos Genéticas/estadística & datos numéricos , Modelos Animales de Enfermedad , Genómica/métodos , Humanos , Trastornos Mentales/genética , Polimorfismo de Nucleótido Simple/genética , Proteína Reelina , Esquizofrenia/diagnósticoRESUMEN
Self-esteem and well-being are important for successful aging, and some evidence suggests that self-esteem and well-being are associated with hippocampal volume, cognition and stress responsivity. Whereas most of this evidence is based on studies on older adults, we investigated self-esteem, well-being and hippocampal volume in 474 male middle-aged twins. Self-esteem was significantly positively correlated with hippocampal volume (0.09, P = 0.03 for left hippocampus, 0.10, P = 0.04 for right). Correlations for well-being were not significant (Ps > 0.05). There were strong phenotypic correlations between self-esteem and well-being (0.72, P < 0.001) and between left and right hippocampal volume (0.72, P < 0.001). In multivariate genetic analyses, a two-factor additive genetic and unique environmental (AE) model with well-being and self-esteem on one factor and left and right hippocampal volumes on the other factor fits the data better than Cholesky, independent pathway or common pathway models. The correlation between the two genetic factors was 0.12 (P = 0.03); the correlation between the environmental factors was 0.09 (P > 0.05). Our results indicate that largely different genetic and environmental factors underlie self-esteem and well-being on one hand and hippocampal volume on the other.
Asunto(s)
Hipocampo/anatomía & histología , Tamaño de los Órganos/fisiología , Satisfacción Personal , Autoimagen , Envejecimiento/genética , Envejecimiento/psicología , Humanos , Masculino , Persona de Mediana Edad , Modelos PsicológicosRESUMEN
There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.
Asunto(s)
Biomarcadores/sangre , Deluciones/genética , Genómica/métodos , Alucinaciones/genética , Trastornos Psicóticos/genética , Adulto , Estudios de Casos y Controles , Deluciones/sangre , Deluciones/complicaciones , Femenino , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Alucinaciones/sangre , Alucinaciones/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Trastornos Psicóticos/sangre , Trastornos Psicóticos/complicaciones , Esquizofrenia/sangre , Esquizofrenia/complicaciones , Esquizofrenia/genéticaRESUMEN
Omega-3 fatty acids have been proposed as an adjuvant treatment option in psychiatric disorders. Given their other health benefits and their relative lack of toxicity, teratogenicity and side effects, they may be particularly useful in children and in females of child-bearing age, especially during pregnancy and postpartum. A comprehensive mechanistic understanding of their effects is needed. Here we report translational studies demonstrating the phenotypic normalization and gene expression effects of dietary omega-3 fatty acids, specifically docosahexaenoic acid (DHA), in a stress-reactive knockout mouse model of bipolar disorder and co-morbid alcoholism, using a bioinformatic convergent functional genomics approach integrating animal model and human data to prioritize disease-relevant genes. Additionally, to validate at a behavioral level the novel observed effects on decreasing alcohol consumption, we also tested the effects of DHA in an independent animal model, alcohol-preferring (P) rats, a well-established animal model of alcoholism. Our studies uncover sex differences, brain region-specific effects and blood biomarkers that may underpin the effects of DHA. Of note, DHA modulates some of the same genes targeted by current psychotropic medications, as well as increases myelin-related gene expression. Myelin-related gene expression decrease is a common, if nonspecific, denominator of neuropsychiatric disorders. In conclusion, our work supports the potential utility of omega-3 fatty acids, specifically DHA, for a spectrum of psychiatric disorders such as stress disorders, bipolar disorder, alcoholism and beyond.
Asunto(s)
Alcoholismo/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Trastorno Bipolar/tratamiento farmacológico , Ácidos Docosahexaenoicos/farmacología , Genómica/métodos , Estrés Psicológico/tratamiento farmacológico , Alcoholismo/genética , Animales , Conducta Animal/fisiología , Trastorno Bipolar/genética , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/sangre , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Ratas , Estrés Psicológico/genéticaRESUMEN
BACKGROUND: The APOE epsilon4 allele is an established risk factor for Alzheimer disease (AD), yet findings are mixed for how early its effects are manifest. One reason for the mixed results could be the presence of interaction effects with other AD risk factors. Increasing evidence indicates that testosterone may play a significant role in the development of AD. The aim of the present study was to examine the potential interaction of testosterone and APOE genotype with respect to hippocampal volume in middle age. METHODS: Participants were men from the Vietnam Era Twin Study of Aging (n = 375). The mean age was 55.9 years (range 51-59). Between-group comparisons were performed utilizing a hierarchical linear mixed model that adjusted for the nonindependence of twin data. RESULTS: A significant interaction was observed between testosterone and APOE genotype (epsilon4-negative vs epsilon4-positive). Those with both low testosterone (> or =1 SD below the mean) and an epsilon4-positive status had the smallest hippocampal volumes, although comparisons with normal testosterone groups were not significant. However, individuals with low testosterone and epsilon4-negative status had significantly larger hippocampal volumes relative to all other groups. A main effect of APOE genotype on hippocampal volume was observed, but only when the APOE-by-testosterone interaction was present. CONCLUSIONS: These findings demonstrate an interaction effect between testosterone and the APOE epsilon4 allele on hippocampal volume in middle-aged men, and they may suggest 2 low testosterone subgroups. Furthermore, these results allude to potential gene-gene interactions between APOE and either androgen receptor polymorphisms or genes associated with testosterone production.
Asunto(s)
Apolipoproteínas E/genética , Hipocampo/anatomía & histología , Testosterona/sangre , Envejecimiento/genética , Alelos , Apolipoproteínas E/metabolismo , Genotipo , Hipocampo/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Polimorfismo Genético , Estados Unidos , Veteranos , Guerra de VietnamRESUMEN
Patients with schizophrenia frequently display neurocognitive dysfunction, and genetic studies suggest it to be an endophenotype for schizophrenia. Genetic studies of such traits may thus help elucidate the biological pathways underlying genetic susceptibility to schizophrenia. This study aimed to identify loci influencing neurocognitive performance in schizophrenia. The sample comprised of 1207 affected individuals and 1035 unaffected individuals of Han Chinese ethnicity from 557 sib-pair families co-affected with DSM-IV (Diagnostic and Statistical Manual, Fourth Edition) schizophrenia. Subjects completed a face-to-face semi-structured interview, the continuous performance test (CPT) and the Wisconsin card sorting test (WCST), and were genotyped with 386 microsatellite markers across the genome. A series of autosomal genome-wide multipoint nonparametric quantitative trait loci (QTL) linkage analysis were performed in affected individuals only. Determination of genome-wide empirical significance was performed using 1000 simulated genome scans. One linkage peak attaining genome-wide significance was identified: 12q24.32 for undegraded CPT hit rate [nonparametric linkage z (NPL-Z) scores = 3.32, genome-wide empirical P = 0.03]. This result was higher than the peak linkage signal obtained in the previous genome-wide scan using a dichotomous diagnosis of schizophrenia. The identification of 12q24.32 as a QTL has not been consistently implicated in previous linkage studies on schizophrenia, which suggests that the analysis of endophenotypes provides additional information from what is seen in analyses that rely on diagnoses. This region with linkage to a particular neurocognitive feature may inform functional hypotheses for further genetic studies for schizophrenia.
Asunto(s)
Trastornos del Conocimiento/genética , Trastornos del Conocimiento/psicología , Estudio de Asociación del Genoma Completo , Esquizofrenia/genética , Psicología del Esquizofrénico , Pueblo Asiatico , Cromosomas/genética , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Ligamiento Genético , Sitios Genéticos , Marcadores Genéticos , Humanos , Repeticiones de Microsatélite , Pruebas Neuropsicológicas , Desempeño Psicomotor/fisiología , Hermanos , Taiwán/epidemiologíaRESUMEN
Chromosome 6p is one of the most commonly implicated regions in the genome-wide linkage scans of schizophrenia, whereas further association studies for markers in this region were inconsistent likely due to heterogeneity. This study aimed to identify more homogeneous subgroups of families for fine mapping on regions around markers D6S296 and D6S309 (both in 6p24.3) as well as D6S274 (in 6p22.3) by means of similarity in neurocognitive functioning. A total of 160 families of patients with schizophrenia comprising at least two affected siblings who had data for eight neurocognitive test variables of the continuous performance test (CPT) and the Wisconsin card sorting test (WCST) were subjected to cluster analysis with data visualization using the test scores of both affected siblings. Family clusters derived were then used separately in family-based association tests for 64 single nucleotide polymorphisms (SNPs) covering the region of 6p24.3 and 6p22.3. Three clusters were derived from the family-based clustering, with deficit cluster 1 representing deficit on the CPT, deficit cluster 2 representing deficit on both the CPT and the WCST, and a third cluster of nondeficit. After adjustment using false discovery rate for multiple testing, SNP rs13873 and haplotype rs1225934-rs13873 on BMP6-TXNDC5 genes were significantly associated with schizophrenia for the deficit cluster 1 but not for the deficit cluster 2 or nondeficit cluster. Our results provide further evidence that the BMP6-TXNDC5 locus on 6p24.3 may play a role in the selective impairments on sustained attention of schizophrenia.
Asunto(s)
Mapeo Cromosómico/métodos , Cromosomas Humanos Par 6/genética , Trastornos del Conocimiento/genética , Predisposición Genética a la Enfermedad/genética , Esquizofrenia/complicaciones , Esquizofrenia/genética , Adulto , Anciano , Proteína Morfogenética Ósea 6/genética , Encéfalo/metabolismo , Encéfalo/fisiopatología , Análisis por Conglomerados , Trastornos del Conocimiento/fisiopatología , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Proteína Disulfuro Isomerasas/genética , Esquizofrenia/fisiopatología , Psicología del EsquizofrénicoRESUMEN
A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.